Substituted indoles

ABSTRACT

Compounds of the formula I  
                 
 
     are suitable for preparing pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of NFκB is involved.

[0001] This application claims the benefit of foreign priority under 35U.S.C. §119 of German patent application no. 19951360.0, filed on Oct.26, 1999 the contents of which are incorporated by reference herein.

[0002] The invention relates to novel substituted indoles, to processesfor their preparation and to their use as pharmaceuticals.

[0003] The application WO 94/12478 describes, inter alia, indolederivatives which inhibit blood platelet aggregation.

[0004] NFκB is a heterodimeric transcription factor which can activate alarge number of genes which code, inter alia, for proinflammatorycytokines such as IL-1, IL-2, TNFα or IL-6. NFκB is present in thecytosole of cells, complexed with its naturally occurring inhibitor IκB.The stimulation of cells, for example by cytokines, leads to thephosphorylation and subsequent proteolytic degradation of IκB. Thisproteolytic degradation leads to the activation of NFκB, whichsubsequently migrates into the nucleus of the cell and there activates alarge number of proinflammatory genes.

[0005] In disorders such as rheumatoid arthritis (in the case ofinflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer'sdisease or atherosclerosis, NFκB is activated beyond the normal extent.The inhibition of NFκB is also of benefit in cancer therapy, since it isemployed there for the reinforcement of the cytostatic therapy. It waspossible to show that pharmaceuticals such as glucocorticoids,salicylates or gold salts, which are employed in rheumatic therapy,intervene in an inhibitory manner at various points in theNFκB-activating signal chain or interfere directly with thetranscription of the genes.

[0006] The first step in the signal cascade mentioned is the degradationof IκB. This phosphorylation is regulated by the specific IκB kinase. Todate, no inhibitors are known which specifically inhibit IκB kinase.

[0007] In an attempt to obtain active compounds for the treatment ofrheumatoid arthritis (in the case of inflammation), osteoarthritis,asthma, cardiac infarct, Alzheimer's. disease, carcinomateous disorders(potentiation of cytotoxic therapies) or atherosclerosis, it has nowbeen found that the indole derivatives according to the invention arepotent and very specific inhibitors of IκB kinase.

[0008] The invention therefore relates to the compounds of the formula I

[0009] and/or a stereoisomeric form of the compound of the formula Iand/or a physiologically acceptable salt of the compound of the formulaI, where one of the substituents R¹, R², R³ and R⁴ is a radical of theformula II

[0010] in which D is —C(O)—, —S(O)— or —S(O)₂—,

[0011] R⁷ is hydrogen or —(C₁-C₄)-alkyl,

[0012] R⁸ is R⁹ or the characteristic radical of an amino acid,

[0013] R⁹ is 1. aryl, where aryl is unsubstituted or substituted,

[0014] 2. heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or substituted,

[0015] 3. heterocycle having 5 to 12 ring members, where heterocycle isunsubstituted or substituted, or

[0016] 4. —(C₁-C₆)-alkyl, where alkyl is straight-chain or branched andis unsubstituted or mono-, di- or trisubstituted, independently of oneanother, by

[0017] 4.1 aryl, where aryl is unsubstituted or substituted,

[0018] 4.2 heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or substituted,

[0019] 4.3 heterocycle having 5 to 12 ring members, where heterocycle isunsubstituted or substituted,

[0020] 4.4 —O—R¹⁰,

[0021] 4.5 ═O,

[0022] 4.6 halogen,

[0023] 4.7 —CN,

[0024] 4.8 —CF₃,

[0025] 4.9 —S(O)_(x)—R¹⁰, where x is the integer zero, 1 or 2,

[0026] 4.10 —C(O)—O—R¹⁰,

[0027] 4.11 —C(O)—N(R¹⁰)₂,

[0028] 4.12 —N(R¹⁰)₂,

[0029] 4.13 —(C₃-C₆)-cycloalkyl,

[0030] 4.14 radical of the formula

[0031]  or

[0032] 4.15 radical of the formula

[0033] R¹⁰ is a) hydrogen,

[0034] b) —(C₁-C₆)-alkyl, where alkyl is unsubstituted or mono- totrisubstituted, independently of one another, by

[0035] 1. aryl,

[0036] 2. heteroaryl having 5 to 14 ring members,

[0037] 3. heterocycle having 5 to 12 ring members,

[0038] 4. halogen,

[0039] 5. —N—(C₁-C₆)_(n)-alkyl, where n is the integer zero, 1 or 2 andalkyl is unsubstituted or mono-, di- or trisubstituted, independently ofone another, by halogen or by —C(O)—OH, or

[0040] 6. —C(O)—OH,

[0041] c) aryl,

[0042] d) heteroaryl having 5 to 14 ring members or

[0043] e) heterocycle having 5 to 12 ring members and, in the case of(R¹⁰)₂, R¹⁰, independently of one another, has the meaning of a) to e),

[0044] Z is 1. aryl, where aryl is unsubstituted or substituted,

[0045] 2. heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or substituted,

[0046] 3. heterocycle having 5 to 12 ring members, where heterocycle isunsubstltuted or substituted, or

[0047] 4. —C(O)—R¹¹, where

[0048] R¹¹ is 1. —O—R¹⁰ or

[0049] 2. —N(R¹⁰)₂, or

[0050] R⁷ and R⁸ form, together with the nitrogen atom and carbon atomto which they are each bonded, a heterocyclic ring of the formula IIa,

[0051] in which D, Z and R¹¹ are as defined in formula II,

[0052] A is a nitrogen atom or the radical —CH₂—,

[0053] B is an oxygen atom, sulfur atom, nitrogen atom or the radical—CH₂—,

[0054] X is an oxygen atom, sulfur atom, nitrogen atom or the radical—CH₂—,

[0055] Y is absent or is an oxygen atom, sulfur atom, sulfoatom or theradical —CH₂—, or

[0056] X and Y together form a phenyl, 1,2-diazine, 1,3-diazine or a1,4-diazine radical,

[0057] where the ring system formed by N, A, X, Y, B and the carbon atomcontains not more than one oxygen atom, X is not an oxygen atom, sulfuror nitrogen atom if A is a nitrogen atom, contains not more than onesulfur atom, contains 1, 2, 3 or 4 nitrogen atoms and where an oxygenand sulfur atom do not occur at the same time,

[0058] where the ring system formed by N, A, X, Y, B and the carbon atomis unsubstituted or mono- to trisubstituted, independently of oneanother, by —(C₁-C₈)-alkyl, unsubstituted or mono- to disubstituted by

[0059] 1.1. —OH,

[0060] 1.2. (C₁-C₈)-alkoxy,

[0061] 1.3. halogen,

[0062] 1.4. —NO₂,

[0063] 1.5. —NH₂,

[0064] 1.6. —CF₃,

[0065] 1.7. —OH,

[0066] 1.8 methylenedioxy,

[0067] 1.9 —C(O)—CH₃,

[0068] 1.10. —CH(O),

[0069] 1.11. —CN,

[0070] 1.12. —C(O)—OH,

[0071] 1.13. —C(O)—NH₂,

[0072] 1.14. (C₁-C₄)-alkoxycarbonyl,

[0073] 1.15. phenyl,

[0074] 1.16. phenoxy,

[0075] 1.17. benzyl,

[0076] 1.18. benzyloxy or

[0077] 1.19. tetrazolyl, or

[0078] R⁸ and Z form, together with the carbon atoms to which they eachare bonded, a heterocyclic ring of the formula IIc,

[0079] in which D, R⁷ and R¹⁰ are as defined in formula II,

[0080] T is an oxygen atom, sulfur atom, nitrogen atom or the radical—CH₂—,

[0081] W is an oxygen atom, sulfur atom, nitrogen atom or the radical—CH₂—,

[0082] V is absent or is an oxygen atom, sulfur atom, nitrogen atom orthe radical —CH₂—, or

[0083] T and V or V and W together form a phenyl, 1,2-diazine,1,3-diazine or a 1,4-diazine radical,

[0084] where the ring system formed by N, T, V, W and two carbon atomscontains not more than one oxygen atom, not more than one sulfur atomand 1, 2, 3 or 4 nitrogen atoms, where an oxygen atom and sulfur atom donot occur at the same time, and where the ring system formed by N, T, V,W and two carbon atoms is unsubstituted or mono- to trisubstituted,independently of one another, by the substituents defined above under1.1. to 1.19.,

[0085] and the respective other substituents R¹, R², R³ and R⁴independently of one another are

[0086] 1. hydrogen,

[0087] 2. halogen,

[0088] 3. aryl, where aryl is unsubstituted or substituted,

[0089] 4. heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or substituted,

[0090] 5. heterocycle having 5 to 12 ring members, where heterocycle isunsubstituted or substituted,

[0091] 6. —(C₁-C₆)-alkyl,

[0092] 7. —CN,

[0093] 8. —O—R¹⁰,

[0094] 9. —N(R¹⁰)₂,

[0095] 10. —S(O)_(x)—R¹⁰, where x is the integer zero, 1 or 2, or

[0096] 11. —CF₃,

[0097] R⁵ is 1. hydrogen,

[0098] 2. —OH or

[0099] 3. ═O, and

[0100] R⁶ is 1. aryl, where aryl is unsubstituted or substituted,

[0101] 2. heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or mono- to trisubstituted, or

[0102] 3. heterocycle having 5 to 12 ring members, where heterocycle isunsubstituted or mono- to trisubstituted.

[0103] A preferred compound of the formula I is one where one of thesubstituents R¹, R², R³ and R⁴ is a radical of the formula II, in which

[0104] D is —C(O)—,

[0105] R⁷ is hydrogen or —(C₁-C₄)-alkyl,

[0106] R⁸ is 1. —(C₁-C₄)-alkyl, where alkyl is straight-chain orbranched and is mono- or disubstituted, independently of one another, by

[0107] 1.1 heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or substituted,

[0108] 1.2 heterocycle. having 5 to 12 ring members, where heterocycleis unsubstituted or substituted,

[0109] 1.3 —O—R¹⁰,

[0110] 1.4 —S(O)_(x)—R¹⁰, where x is the integer zero, 1 or 2,

[0111] 1.5 —N(R¹⁰)₂,

[0112] 1.6 radical of the formula

[0113] or

[0114] 1.7 radical of the formula

[0115] or

[0116] 2. is the characteristic radical of an amino acid,

[0117] R⁹ is 1. R⁸,

[0118] 2. —(C₁-C₄)-alkyl, where alkyl is straight-chain or branched andis, independently of one another, mono-, di- or trisubstituted by

[0119] 2.1 aryl, where aryl is unsubstituted or substituted,

[0120] 2.2 halogen,

[0121] 2.3 —CN or

[0122] 2.4 —CF₃ or

[0123] 3. aryl, where aryl is unsubstituted or substituted,

[0124] R¹⁰ is a) hydrogen,

[0125] b) —(C₁-C₆)-alkyl, where alkyl is unsubstituted or mono- totrisubstituted, independently of one another, by

[0126] 1. aryl,

[0127] 2. heteroaryl having 5 to 14 ring members,

[0128] 3. heterocycle having 5 to 12 ring members,

[0129] 4. halogen,

[0130] 5. —N—(C₁-C₆)_(n)-alkyl, where n is the integer zero, 1 or 2 andalkyl is unsubstituted or mono-, di- or trisubstituted, independently ofone another, by halogen or by —C(O)—OH, or

[0131] 6. —C(O)—OH,

[0132] c) aryl,

[0133] d) heteroaryl having 5 to 14 ring members or

[0134] e) heterocycle having 5 to 12 ring members and, in the case of(R¹⁰)₂, R¹⁰, independently of one another, has the meaning of a) to e),

[0135] Z is 1. 1,3,4-oxadiazole, where 1,3,4-oxadiazole is unsubstitutedor mono- to trisubstituted by —NH₂, OH or —(C₁-C₄)-alkyl or

[0136] 2. —C(O)—R¹¹, in which

[0137] R¹¹ is 1. —O—R¹⁰ or

[0138] 2. —N(R¹⁰)₂, or

[0139] R⁷ and R⁸ form, together with the nitrogen atom and carbon atomto which they are each bonded, a ring of the formula IIa selected fromthe group consisting of pyrrole, pyrroline, indole, pyrrolidine,pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine,piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine,imidazolidine, oxazole, purine, isoxazole, 2-isoxazolidine,isoxazolidine, morpholine, isothiazole, thiazole, thiadiazole,benzimidazole, thiomorpholine, isothiazolidine, indazole, quinoline,triazole, phthalazine, quinazoline, quinoxaline, pteridine,tetrahydroquinoline, isoquinoline, 1,2,3,5-oxathiadiazole 2-oxides,tetrazole, oxadiazolones, isoxazolones, triazolones,oxadiazolidinediones, triazoles, which are substituted by F, —CN, —CF₃or —C(O)—O—(C₁-C₄)-alkyl, 3-hydroxypyrrole-2,4-diones,5-oxo-1,2,4-thiadiazoles and tetrahydroisoquinoline, or

[0140] R⁸ and Z form, together with the carbon atoms to which they areeach bonded, a ring of the formula IIc selected from the groupconsisting of pyrrole, pyrroline, pyrrolidine, pyridine, piperidine,piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole,imidazole, pyrazoline, 1,3,4-oxadiazole, imidazoline, pyrazolidine,imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine,morpholine, isothiazole, thiazole, isothiazolidine, tetrazole,thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline,triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine,indole, tetrahydroquinoline, triazolones, tetrahydroisoquinoline,1,2,3,5-oxathiadiazole 2-oxides, oxadiazolones, isoxazolones,oxadiazolidindiones, triazoles, which are substituted by F, —CN, —CF₃ or—C(O)—O—(C₁-C₄)-alkyl, 3-hydroxypyrrole-2,4-diones,5-oxo-1,2,4-thiadiazoles and isoquinoline, and

[0141] the other substituents R¹, R², R³ and R⁴ in each caseindependently of one another are

[0142] 1. hydrogen,

[0143] 2. halogen,

[0144] 3. aryl, where aryl is unsubstituted or substituted,

[0145] 4. heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or substituted,

[0146] 5. heterocycle having 5 to 12 ring members, where heterocycle isunsubstituted or substituted, or

[0147] 6. —(C₁-C₆)-alkyl,

[0148] 7. —CN,

[0149] 8. —CF₃,

[0150] 9. —O—R¹⁰,

[0151] 10. —N(R¹⁰)₂, or

[0152] 11. —S(O)_(x)—R¹⁰, where x is the integer zero, 1 or 2,

[0153] R⁵ is hydrogen and

[0154] R⁶ is 1. phenyl, mono- or disubstituted, independently of oneanother, by

[0155] 1.1 —CN,

[0156] 1.2 —CF₃ or

[0157] 1.3 halogen,

[0158] 1.4 —O—R¹⁰,

[0159] 1.5 —N(R¹⁰)₂,

[0160] 1.6 —NH—C(O)—R¹¹,

[0161] 1.7 —S(O)_(x)—R¹⁰, where x is the integer zero, 1 or 2,

[0162] 1.8 —C(O)—R¹¹ or

[0163] 1.9 —(C₁-C₄)-alkyl-NH₂,

[0164] 2. heteroaryl having 5 to 14 ring members, where heteroaryl isunsubstituted or mono-, di- or trisubstituted, independently of oneanother, by the substituents defined above under 1.1 to 1.9 or

[0165] 3. heterocycle having 5 to 12 ring members, where heterocycle isunsubstituted or mono-, di- or trisubstituted, independently of oneanother, by the substituents defined above under 1.1 to 1.9.

[0166] A particularly preferred compound of the formula I is one whereone of the substituents R¹, R², R³ and R⁴ is a radical of the formulaII, in which

[0167] D is —C(O)—,

[0168] R⁷ is hydrogen,

[0169] Z is —C(O)—OH or —C(O)—NH₂,

[0170] R⁸ is 1. —(C₁-C₄)-alkyl, where alkyl is straight-chain orbranched and is mono- or disubstituted, independently of one another, by

[0171] 1.1 —S(O)—R¹⁰, where R¹⁰ is as defined below,

[0172] 1.2 —N(R¹⁰)₂, where R¹⁰ is as defined below, or

[0173] 1.3 pyrrole or

[0174] 2. is the characteristic radical of an amino acid,

[0175] R¹⁰ is a) hydrogen,

[0176] b) —(C₁-C₆)-alkyl, where alkyl is unsubstituted or mono- totrisubstituted, independently of one another, by halogen,

[0177] c) phenyl, where phenyl is unsubstituted or mono- totrisubstituted, independently of one another, by halogen or—(C₁-C₄)-alkyl,

[0178] in the case of (R¹⁰)₂, R¹⁰, independently of one another, has themeaning of a) to c), the other substituents R¹, R², R³ and R⁴ in eachcase are hydrogen,

[0179] R⁵ is hydrogen,

[0180] R⁶ is phenyl or pyridine, and

[0181] R⁹ is 1. hydrogen,

[0182] 2. —(C₁-C₄)-alkyl, where alkyl is straight-chain or branched and,independently of one another, mono-, di- or trisubstituted by —C(O)—OH,—OH or —C(O)—NH₂, or

[0183] 3. phenyl, where phenyl is unsubstituted or mono- totrisubstituted, independently of,one another, by halogen or—(C₁-C₄)-alkyl.

[0184] The term “halogen” is understood as meaning fluorine, chlorine,bromine or iodine. The terms “(C₁-C₈)-alkyl”, “(C₁-C₆)-alkyl” or“(C₁-C₄)-alkyl” are understood as meaning hydrocarbon radicals whosecarbon chain is straight-chain or branched and contains 1 to 8, 1 to 6and 1 to 4 carbon atoms, respectively. Cyclic alkyl radicals are, forexample, 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

[0185] The term “R⁷ and R⁸ form, together with the nitrogen atom andcarbon atom to which they are each bonded, a heterocyclic ring of theformula IIa”, is understood as meaning radicals which are derived frompyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole,isoxazole, tetrazole, isoxazoline, isoxazolidine, morpholine, thiazole,isothiazole, isothiazoline, purine, isothiazolidine, thiomorpholine,pyridine, piperidine, pyrazine, piperazine, pyrimidine, pyridazine,indole, isoindole, indazole, benzimidazole, phthalazine, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, pteridine,triazolones, tetrazole, 1,2,3,5-oxathiadiazole 2-oxides, oxadiazolones,isoxazolones, oxadiazolidinediones, triazoles, which are substituted byF, —CN, —CF₃ or —C(O)—O—(C₁-C₄)-alkyl, 3-hydroxypyrrole-2,4-diones,5-oxo-1,2,4-thiadiazoles, imidazolidine, carboline and benzo-fusedderivatives of these heterocycles.

[0186] The term aryl is understood as meaning aromatic hydrocarbonradicals having 6 to 14 carbon atoms in the ring. (C₆-C₁₄)-Aryl radicalsare, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl,biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl,anthryl or fluorenyl. Biphenylyl radicals, naphthyl radicals and, inparticular, phenyl radicals are preferred aryl radicals. Aryl radicals,in particular phenyl radicals, can be monosubstituted orpolysubstituted, preferably monosubstituted, disubstituted ortrisubstituted, by identical or different radicals, preferably byradicals from the group consisting of (C₁-C₈)-alkyl, in particular(C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy, halogen,nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C₁-C₄)-alkyl such ashydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, tetrazolyl.The same applies, for example, to radicals such as arylalkyl orarylcarbonyl. Arylalkyl radicals are, in particular, benzyl and also 1-and 2-naphthylmethyl, 2-, 3- and 4-biphenylylmethyl and9-flubrenylmethyl. Substituted arylalkyl radicals are, for example,benzyl radicals and naphthylmethyl radicals substituted in the arylmoiety by one or more (C₁-C₈)-alkyl radicals, in particular(C₁-C₄)-alkyl radicals, for example 2-, 3- and 4-methylbenzyl,4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl,pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7- and 8-methyl-1-naphthylmethyl,1-, 3-, 4-, 5-, 6-, 7- and 8-methyl-2-naphthylmethyl, by one or more(C₁-C₈)-alkoxy radicals, in particular (C₁-C₄)-alkoxy radicals, benzylradicals and naphthylmethyl radicals substituted in the aryl moiety, forexample 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl,3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, nitrobenzyl radicals,for example 2-, 3- and 4-nitrobenzyl, halobenzyl radicals, for example2-, 3- and 4-chloro- and 2-, 3- and 4-fluorobenzyl, 3,4-dichlorobenzyl,pentafluorobenzyl, trifluoromethylbenzyl radicals, for example 3- and3,4-trifluoromethylbenzyl or 3,5-bis(trifluoromethyl)benzyl.

[0187] In monosubstituted phenyl radicals, the substituent can belocated in the 2-position, the 3-position or the 4-position.Disubstituted phenyl can be substituted in the 2,3-position, the2,4-position, the 2,5-position, the 2,6-position, the 3,4-position orthe 3,5-position. In trisubstituted phenyl radicals, the substituentscan be located in the 2,3,4-position, the 2,3,5-position, the2,4,5-position, the 2,4,6-position, the 2,3,6-position or the3,4,5-position.

[0188] The explanations for the aryl radicals apply accordingly todivalent arylene radicals, for example to phenylene radicals which canbe present, for example, as 1,4-phenylene or as 1,3-phenylene.

[0189] Phenylene-(C₁-C₆)-alkyl is in particular phenylenemethyl(—C₆H₄—CH₂—) and phenyleneethyl, (C₁-C₆)-alkylenephenyl is in particularmethylenephenyl (—CH₂—C₆H₄—). Phenylene-(C₂-C₆)-alkenyl is in particularphenyleneethenyl and phenylenepropenyl.

[0190] The expression “heteroaryl having 5 to 14 ring members”represents a radical of a monocyclic or polycyclic aromatic systemhaving 5 to 14 ring members, which contains 1, 2, 3, 4 or 5 heteroatomsas ring members. Examples of heteroatoms are N, O and S. If a number ofheteroatoms are contained, these can be identical or different.Heteroaryl radicals can likewise be monosubstituted or polysubstituted,preferably monosubstituted, disubstituted or trisubstituted, byidentical or different radicals from the group consisting of(C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, inparticular (C₁-C₄)-alkoxy, halogen, nitro, —N(R¹⁰)₂, trifluoromethyl,hydroxyl, hydroxy-(C₁-C₄)-alkyl such as hydroxymethyl or 1-hydroxyethylor 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano,hydroxycarbonyl, aminocarbonyl, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy,benzyl, benzyloxy, tetrazolyl. Heteroaryl having 5 to 14 ring memberspreferably represents a monocyclic or bicyclic aromatic radical whichcontains 1, 2, 3 or 4, in particular 1, 2 or 3, identical or differentheteroatoms from the group consisting of N, O and S and which can besubstituted by 1, 2, 3 or 4, in particular 1 to 3, identical ordifferent substituents from the group consisting of (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, fluorine, chlorine, nitro, —N(R¹⁰)₂, trifluoromethyl,hydroxyl, hydroxy-(C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl, phenyl,phenoxy, benzyloxy and benzyl. Heteroaryl particularly preferablyrepresents a monocyclic or bicyclic aromatic radical having 5 to 10 ringmembers, in particular a 5-membered or 6-membered monocyclic aromaticradical which contains 1, 2 or 3, in particular 1 or 2, identical ordifferent heteroatoms from the group consisting of N, O and S and can besubstituted by 1 or 2 identical or different substituents from the groupconsisting of (C₁-C₄)-alkyl, halogen, hydroxyl, —N(R¹⁰)₂,(C₁-C₄)-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.

[0191] The expression “heterocycle having 5 to 12 ring members”represents a monocyclic or bicyclic 5-membered to 12-memberedheterocyclic ring which is partly saturated or completely saturated.Examples of heteroatoms are N, O and S. The heterocycle is unsubstitutedor substituted on one or more carbon atoms or on one or more heteroatomsby identical or different substituents. These substituents have beendefined above for the radical heteroaryl. In particular, theheterocyclic ring is monosubstituted or polysubstituted, for examplemonosubstituted, disubstituted, trisubstituted or tetrasubstituted, oncarbon atoms by identical or different radicals from the groupconsisting of (C₁-C₈)-alkyl, for example (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy,for example (C₁-C₄)-alkoxy such as methoxy, phenyl-(C₁-C₄)-alkoxy, forexample benzyloxy, hydroxyl, oxo, halogen, nitro, amino ortrifluoromethyl and/or it is substituted on the ring nitrogen atom(s) inthe heterocyclic ring, by (C₁-C₈)-alkyl, for example (C₁-C₄)-alkyl suchas methyl or ethyl, by optionally substituted phenyl orphenyl-(C₁-C₄)-alkyl, for example benzyl. Nitrogen heterocycles can alsobe present as N-oxides or as quaternary salts.

[0192] Examples of the expressions heteroaryl having 5 to 14 ringmembers or heterocycle having 5 to 12 ring members are radicals whichare derived from pyrrole, furan, thiophene, imidazole, pyrazole,oxazole, isoxazole, thiazqle, isothiazole, tetrazole,1,2,3,5-oxathiadiazole 2-oxides, triazolones, oxadiazolones,isoxazolones, oxadiazolidinediones, triazoles, which are substituted byF, —CN, —CF₃ or —C(O)—O—(C₁-C₄)-alkyl, 3-hydroxypyrrole-2,4-diones,5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, carboline and benzo-fused, cyclopenta-,cyclohexa- or cyclohepta-fused derivatives of these heterocycles.Particularly preferred radicals are 2- or 3-pyrrolyl, phenylpyrrolylsuch as 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl,methylimidazolyl, for example 1-methyl-2-, -4- or -5-imidazolyl,1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-, 3- or5-indolyl, substituted 2-indolyl, for example 1-methyl-, 5-methyl-,5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-2-indolyl,1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl,cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl,1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl,2-benzothienyl, 2-benzoxazolyl or benzothiazolyl or dihydropyridinyl,pyrrolidinyl, for example 2- or 3-(N-methylpyrrolidinyl), piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrothienyl or benzodioxolanyl.

[0193] The structural formula of α-amino acids is as follows:

[0194] The α-amino acids differ from one another by the radical R, whichin the context of the present application is described as a“characteristic radical” of an amino acid.

[0195] In the case where R⁸ is the characteristic radical of an aminoacid, the characteristic radicals employed are preferably those of thefollowing naturally occurring α-amino acids: glycine, alanine, valine,leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine,threonine, cysteine, methionine, asparagine, glutamine, lysine,histidine, arginine, glutamic acid and aspartic acid. Those particularlypreferred are histidine, tryptophan, serine, threonine, cysteine,methionine, asparagine, glutamine, lysine, arginine, glutamic acid andaspartic acid. Preferred characteristic radicals of an amino acid whichare furthermore employed as the radical R⁸ are also non-naturallyoccurring amino acids such as 2-aminoadipic acid, 2-aminobutyric acid,2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyricacid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid,phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine,2-(2-thienyl)-glycine, 2-aminoheptanoic acid, pipecolic acid,hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine,N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine,allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline,3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine,homocysteine, homocysteic acid, homotryptophan, cysteic acid,3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine,2-amino-3-phenylaminopropionic acid, 2-amino-3-phenylaminoethylpropionicacid, phosphinothricine, 4-fluorophenylalanine, 3-fluorophenylalanine,4-fluorophenylalanlne, 3-fluorophenylalanine, 3-fluorophenylalanine,2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine,4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan,5-methoxytryptophan, methionine sulfone, methionine sulfoxide or—NH—NR¹⁰—CON(R¹⁰)₂, which are optionally aiso substituted. In the caseof natural but also of non-naturally occurring amino acids which have afunctional group such as amino, hydroxyl, carboxyl, mercapto, guanidyl,imidazolyl qr indolyl, this group can also be protected.

[0196] Suitable protective groups for this are preferably theN-protective groups customarily used in peptide chemistry, for exampleprotective groups of the urethane type, benzyloxycarbonyl (Z),t-butoxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl(Aloc) or of the acid amide type, in particular formyl, acetyl ortrifluoroacetyl, and of the alkyl type, for example benzyl. In the caseof an imidazole radical in R⁸, for example, the sulfonic acid derivativeof the formula IV employed for the sulfonamide formation is used as aprotective group of the imidazole nitrogen, which can be removed again,in particular in the presence of bases such as aqueous sodium hydroxidesolution.

[0197] The starting substances for the chemical reactions are known orcan be easily prepared by methods known from the literature.

[0198] The invention further relates to a process for preparingcompounds of the formula I and/or a stereoisomeric form of the compoundof the formula I and/or of a physiologically acceptable salt of thecompound of the formula I, which comprises

[0199] a) reacting a compound of the formula IV,

[0200] in which Pg is a suitable protective group (for example methylester), an amide group or a hydroxyl group and Z, R⁷ and R⁸ are asdefined in formula I, with an acyl chloride or an activated ester of thecompound of the formula III,

[0201] where D1 is —COOH or sulfonyl halogen and R⁵, R⁶ and R⁹ are asdefined in formula I, in the presence of a base or, if appropriate, of adehydrating agent in solution and, after removal of the protectivegroup, converting into a compound of the formula I, or

[0202] b) reacting a compound of the formula IVa,

[0203] in which R⁷ and R⁸ are as defined in formula I and E is anN-amino protective group, with its carbonyl group coupled via anintermediate chain L to a polymeric resin of the formula PS, a compoundof the formula V

[0204] resulting, which, after selective removal of the protective groupE, is reacted with a compound of the formula III, where R⁵, R⁶ and R⁹are as defined in formula I, in the presence of a base or, ifappropriate, of a dehydrating agent to give a compound of the formula VI

[0205] and converting the compound of the formula VI, after cleavagefrom the support material, into a compound of the formula I, or

[0206] c) converting a compound of the formula I into a physiologicallyacceptable salt.

[0207] In process variant a), the acid functions of the compounds of theformula IVa are provided with a protective group Pg; this selectivecarboxylic acid derivatization is carried out according to methods suchas are described in Houben-Weyl “Methoden der Org. Chemie” [Methods ofOrganic Chemistry], Volume 15/1. In process variant b), the aminofunctions of the starting compounds of the formula IVa are provided witha protective group E; this selective amino groups derivatization iscarried out according to methods such as are described in Houben-Weyl“Methoden der Org. Chemie” [Methods of Organic Chemistry], Volume 15/1.

[0208] A suitable protective group Pg preferably used for this is thecarboxyl protective groups customary in peptide chemistry, for exampleprotective groups of the alkyl ester type, such as methyl, ethyl,tert-butyl, isopropyl, benzyl, fluorenylmethyl, allyl, aryl ester type,such as phenyl, amide type, such as amide or benzhydrylamine. Suitableprotective groups E used for this are preferably the N-protective groupscustomary in peptide chemistry, for example protective groups of theurethane type, such as benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc),9-fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc) or of theacid amide type, in particular formyl, acetyl or trifluoroacetyl ofalkyl type such as benzyl.

[0209] The (trimethylsilyl)ethoxycarbonyl (Teoc) group has also provenparticularly suitable for this (P. Kociénski, Protecting Groups, ThiemeVerlag 1994).

[0210] The indolecarboxylic acid derivatives were prepared following a.method described in Houben-Weyl “Methoden der Org. Chemie” [Methods ofOrganic Chemistry], Volume E6-2A and E6-2B. Thus, for preparing theindolecarboxylic acid derivatives of the formula III, preference isgiven to reacting hydrazinobenzoic acids and aryl ketones or heteroarylketones in the presence of polyphosphoric acid as solvent at 145° C. Thehydrazinobenzoic acids required are prepared by methods known to theperson skilled in the art, for example from the corresponding benzoicacid anilines. Aryl ketones or heteroaryl ketones are likewise preparedby methods familiar to the person skilled in the art, for example, fromthe corresponding acyl chlorides or nitriles by reaction with, forexample, organometallic compounds.

[0211] For the condensation of the compounds of the formula IV withthose of the formula III, the coupling methods which are well-known perse to the person skilled in the art are advantageously used (see, forexample, Houben-Weyl, Methoden der Organischen Chemie [Methods ofOrganic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag,Stuttgart, 1974). Suitable condensing agents or coupling reagents arecompounds such as carbonyldiimidazole, carbodiimides such asdicyclohexylcarbodiimide or diisopropylcarbodiimide (DIC),O-((cyano(ethoxycarbonyl)methylene)-amino)—N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU) or propane-phosphonic anhydride (PPA).

[0212] The condensations can be carried out under standard conditions.During the condensation, as a rule it is necessary for the non-reactingamino groups present to be protected by reversible protective groups.The same applies to carboxyl groups not involved in the reaction, whichduring the condensation are preferably present as (C₁-C₆)-alkyl esters,benzyl esters or tert-butyl esters. Amino group protection isunnecessary if the amino groups are still present in the form ofprecursors such as nitro groups or cyano groups and are only formed byhydrogenation after the condensation. After the condensation, theprotective groups present are removed in a suitable manner. For example,NO₂ groups (guanidino protection in amino acids), benzyloxycarbonylgroups and benzyl groups in benzyl esters can be removed byhydrogenation. The protective groups of the tert-butyl type are removedacidically, while the 9-fluorenylmethoxycarbonyl radical is removed bysecondary amines.

[0213] The polymeric support designated in the formulae V and VI by PSis a crosslinked polystyrene resin having a linker designated as theintermediate chain L. This linker carries a suitable functional group,for example amine, known, for example, as Rink amide resin, or an OHgroup, known, for example, as Wang resin or Kaiser's oxime resin.Alternatively, other polymeric supports such as glass, cotton orcellulose having various intermediate chains L can be employed.

[0214] The intermediate chain designated by L is covalently bonded tothe polymeric support and allows a reversible, amide-like or ester-likebond with the compound of the formula IVa, which remains stable duringthe further reaction on the bonded compound of the formula IVa; butunder strongly acidic reaction conditions, e.g. mixtures withtrifluoroacetic acid, releases the group located on the linker again.

[0215] The release of the desired compound of the formula I from thelinker can be carried out at various positions in the reaction sequence.

[0216] A. General procedure for the coupling of protectedaminocarboxylic acids of the formula IVa to the solid support:

[0217] The synthesis was carried out in reactors each having a reactionvolume of 15 ml. Each of the reactors was filled with 0.179 g of Rinkamide AM resin (Fmoc-Rink amide AM/Nova-Biochem; loading 0.56 mmol/g;i.e. 0.1 mmol/reactor). For the removal of the Fmoc protective groupfrom the resin, a 30% strength piperidine/DMF solution was metered intoeach reactor and the mixture was shaken for 45 minutes (min). It wasthen filtered and the resin was washed 3 times with dimethylformamide(DMF).

[0218] For the coupling of the protected amino acid, a 0.5 molarsolution of the corresponding Fmoc-amino acid (0.3 mmol in DMF), asolution of HOBt (0.33 mmol in DMF) and a solution of DIC (0.33 mmol inDMF) were each added to the resin thus prepared and the mixture wasshaken at 35° C. for 16 hours (h). The resin was then washed with DMF anumber of times.

[0219] To check the coupling, a few resin beads were removed andsubjected to a KAISER test; in all cases the test was negative.

[0220] The removal of the Fmoc protective group was carried out, asmentioned above, using 30% strength piperidine/DMF solution.

[0221] For the coupling of the benzimidazolecarboxylic acids, a 0.1molar solution of the corresponding 4- or 5-substituted acid (0.4 mmolin DMF); a 0.5 molar solution of the coupling reagent TOTU (0.44 mmol inDMF) and a 0.5 molar solution of DIPEA (0.6 mmol in DMF) were added andthe mixture was shaken at 40° C. for 16 hours. It was then washed anumber of times with DMF.

[0222] To check the reaction, a few beads of resin were again removedand subjected to a KAISER test.

[0223] For the removal of the desired substances from the solid support,the resin was washed a number of times with dichloromethane. Thecleavage solution (50% dichloromethane and 50% of a mixture of 95% TFA,2% H₂O, 3% triisopropylsilane) was then added and the mixture was shakenat room temperature for 1 h. The mixture was filtered and the filtratewas concentrated to dryness. The residue was precipitated with diethylether and filtered.

[0224] The solid residues usually contained the desired products in highpurity or were fractionated, for example, on a reverse phase (eluent: A:H₂O/0.1% TFA, B: acetonitrile/0.1% TFA) using preparative high-pressureliquid chromatography. Lyophilization of the fractions obtained yieldedthe desired products.

[0225] The preparation of physiologically acceptable salts of compoundsof the formula I capable of salt formation, including theirstereoisomeric forms, is carried out in a manner known per se. Withbasic reagents such as hydroxides, carbonates, hydrogencarbonates,alkoxides and also ammonia or organic bases, for example trimethyl- ortriethylamine, ethanolamine or triethanolamine or alternatively basicamino acids, for example lysine, ornithine or arginine, the carboxylicacids form stable alkali metal, alkaline earth metal or optionallysubstituted ammonium salts. If the compounds of the formula I containbasic groups, stable acid addition salts can also be prepared usingstrong acids. For this, both inorganic and organic acids such ashydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic,benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic,cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic,tartaric, succinic or trifluoroacetic acid are suitable.

[0226] The invention also relates to pharmaceuticals which comprise anefficacious amount of at least one compound of the formula I and/or of aphysiologically tolerable salt of the compounds of the formula I and/oran optionally stereoisomeric form of the compounds of the formula I,together with a pharmaceutically suitable and physiologically tolerableexcipient, additive and/or other active compounds and auxiliaries.

[0227] On account of the pharmacological properties, the compoundsaccording to the invention are suitable for the prophylaxis and therapyof all those disorders in whose course an increased activity of IkBkinase is involved. For example, compounds of the present invention areuseful in the treatment of joint inflammation, including arthritis,rheumatoid arthritis and other arthritic conditions such as rheumatoid.spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis,psoriatic arthritis and osteoarthritis. Additionally, the compounds areuseful in the treatment of acute synovitis, tuberculosis,atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome,endotoxaemia, sepsis, septic shock, endotoxic shock, gram negativesepsis, gout, toxic shock syndrome, chronic pulmonary inflammatorydiseases including asthma and adult respiratory distress syndrome,silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejection and leprosy,Furthermore, the compounds are useful in the treatment of:—infectionssuch as viral infections, for example HIV, cytomegalovirus (CMV),influenza, adenovirus and the Herpes group of viruses, parasiticinfections, for example malaria such as cerebral malaria, and yeast andfungal infections, for example fungal meningitis; fever and myalgias dueto infection; AIDS; AIDS related complex (ARC); cachexia secondary toinfection or malignancy: cachexia secondary to acquired immunedeficiency syndrome (AIDS) or to cancer; keloid and scar tissueformation; pyresis; diabetes; and inflammatory bowel diseases such asCrohn's disease and ulcerative colitis. The compounds of the inventionare also useful in the treatment of diseases of or injury to the brainin which over-expression of TNFα has been implicated such as multiplesclerosis, and head trauma. The compounds according to the invention arealso useful in the treatment of psoriasis, Alzheimer's disease,carcinomatous disorders (potentiation of cytotoxic therapies), cardiacinfarct, chronic obstructive pulmonary disease (COPD) and acuterespiratory distress syndrome (ARDS).

[0228] The pharmaceuticals according to the invention are in generaladministered orally or parenterally. Rectal or transdermaladministration is also possible.

[0229] The invention also relates to a process for the production of apharmaceutical, which comprises bringing at least one compound of theformula I into a suitable administration form using a pharmaceuticallysuitable and physiologically tolerable excipient and, if appropriate,further suitable active compounds, additives or auxiliaries.

[0230] Suitable solid or pharmaceutical preparation forms are, forexample, granules, powders, coated tablets, tablets, (micro)capsules,suppositories, syrups, juices, suspensions, emulsions, drops orinjectable solutions, and preparations having protracted release ofactive compound, in whose preparation customary auxiliaries, such asexcipients, disintegrants, binders, coating agents, swelling agents,glidants or lubricants, flavorings, sweeteners and solubilizers areused. Frequently used auxiliaries which may be mentioned are magnesiumcarbonate, titanium dioxide, lactose, mannitol and other sugars, talc,lactoprotein, gelatin, starch, cellulose and its derivatives, animal andvegetable oils such as cod liver oil, sunflower, groundnut or sesameoil, polyethylene glycol and solvents such as, for example, sterilewater and mono- or polyhydric alcohols such as glycerol.

[0231] The pharmaceutical preparations are preferably produced andadministered in dose units, each unit containing as active constituent acertain dose of the compound of the formula I according to theinvention. In the case of solid dose units such as tablets, capsules,coated tablets or suppositories, this dose can be up to approximately1000 mg, preferably from approximately 50 mg to 300 mg and in the caseof injection solutions in ampoule form up to approximately 300 mg,preferably from approximately 10 mg to 100 mg.

[0232] For the treatment of an adult patient weighirg approximately 70kg, depending on the efficacy of the compound according to formula I,daily doses of approximately 20 mg to 1000 mg of active compound,preferably from approximately 100 mg to 500 mg, are indicated. Undercertain circumstances. however, even higher or lower daily doses may beappropriate. The administration of the daily dose can be carried outboth by single administration In the form of an individual dose unit orelse of a number of smaller dose units and by multiple administration ofsubdivided doses at specific intervals.

[0233] As a rule, final products are determined by mass-spectroscopicmethods (FAB-, ESI-MS). Temperatures are given in degrees Celsius, RTmeans room temperature (22-26° C.). Abbreviations used are eitherexplained or correspond to the customary conventions.

EXAMPLES Preparation of Substituted Indolecarboxylic Acids

[0234] Process Variant A)

[0235] 2,3-Diphenyl-1H-indole-5-carboxylic acid:

[0236] 1.96 g (10 mmol) of deoxybenzoin and 1.52 g of 4-hydrazinobenzoicacid were ground in a mortar and then fused in an open flask at 160° C.for 15 minutes (min). The cooled melt was admixed with 100 ml of aceticacid and 30 ml of concentrated hydrochloric acid and heated under refluxfor 3 hours (h). The cooled solution was admixed with water, resultingin the precipitation of the product 2,3-diphenyl-1H-indole-5-carboxylicacid. The product was filtered off with suction and the residue waswashed with water and dried. For purification, the crude product wasstirred with warm toluene, filtered off with suction and dried again.This gave 2,3-diphenyl-1H-indole-5-carboxylic acid.

[0237] Process Variant B)

[0238] 2-Pyridin-4-yl-1H-indole-5-carboxylic acid:

[0239] 20 g of P₂O₅ were admixed with 12.5 ml of H₃PO₄ (85%), resultingin a strong increase of the temperature of the reaction mixture. Thereaction mixture was then cooled to 60° C., and 8.90 g (65.84 mmol) of4-propionylpyridine and 4.20 g (27.60 mmol) of 4-hydrazinobenzoic acidwere added. The mixture was then stirred at 145° C. for 45 min. Thereaction mixture was poured into water, resulting in the precipitationof the yellow product 2-pyridin4-yl-1H-indole-5-carboxylic acid. Thisprecipitate was filtered off with suction and washed with water untilneutral. The 2-pyridin-4-yl-1H-indole-5-carboxylic acid, which wasobtained by this method in quantitative yield, was used without furtherpurification for coupling with amino acid derivatives.

[0240] Coupling of amino acid derivatives with substitutedindolecarboxylic acid derivatives.

[0241] Process Variant C)

Example 1

[0242]N-(1-Carbamoyl-3-phenylpropyl)-2,3-diphenyl-1H-indole-5-carboxamide:

[0243] 0.16 g (0.5 mmol) of 2,3-diphenyl-1H-indole-5-carboxylic acid(see process variant A) was dissolved at RT in 10 ml of drydimethylformamide (DMF) and admixed successively with 0.11 g (0.5 mmol)of L-homophenylalaninamide hydrochloride, 0.16 g of TOTU(O-[(cyano(ethoxycarbonyl)-methylidene)amino-1,1,3,3-tetramethyl]uroniumtetrafluoroborate) and 0.14 ml (1 mmol) of diisopropylamine. Thereaction mixture was stirred at RT for 6 h and then concentrated underreduced pressure, and the residue was dissolved in ethyl acetate. Theorganic phase was washed successively with water, saturated sodiumcarbonate solution, water and saturated sodium chloride solution, driedover magnesium sulfate, filtered and concentrated under reducedpressure. This gaveN-(1-carbamoyl-3-phenylpropyl)-2,3-diphenyl-1H-indole-5-carboxamide ofmelting point 120° C. to 125° C.

Example 7

[0244]N-(1-Carbamoyl-3-pyrrol-1-ylpropyl)-3-methyl-2-pyridin-4-yl-1H-indole-5-carboxamide

[0245] 0.13 g (0.5 mmol) of3-methyl-2-pyridin-4-yl-1H-indole-5-carboxylic acid (see process variantA) was dissolved at RT in 10 ml of dry dimethyl formamide (DMF) andmixed successively with 0.083 g (0.5 mmol) of4-(1-pyrrolyl)-L-2-benzylaxycarbonylaminobutyramide, 0.16 g (0.5 mmol)of TOTU(O[(cyano(ethoxycarbonyl)methylidene)amino-1,1,3,3,-tetramethyl]uroniumtetrafluoroborate) and 0.14 ml (1 mmol) of ethyl diisopropylamine. Thereaction mixture was stirred at RT for 6 h and then concentrated underreduced pressure, and the residue was dissolved in ethyl acetate. Theorganic phase was washed successively with water, saturated sodiumcarbonate solution, water and saturated sodium chloride solution, driedover magnesium sulfate, filtered and concentrated under reducedpressure. Purification was carried out by prep. HPLC.

[0246] a: 4-(1-Pyrrolyl)-L-2-benzyloxycarbonylaminobutyric acid

[0247] A solution, flushed with argon, of 1.25 g (5.0 mmol) ofN_(α)-Z-L-2,4-diaminobutyric acid in 60 ml of water was admixed with0.66 g (5.0 mmol) of 2,5-dimethoxytetrahydrofuran, followed by additionof 1.7 ml of glacial acetic acid, and the mixture was stirred at 20° C.for 12 h. The reaction mixture was extracted repeatedly with ethylacetate, the organic phases were combined and dried with sodium sulfateand the filtrate was concentrated under reduced pressure. The crudeproduct was purified by flash chromatography over silica gel(CH₂Cl₂/CH₃OH/CH₃COOH:100/5/1). Removal of the mobile phase gave 1.3 g(87%) of 4-(1-pyrrolyl)-L-2-benzyloxycarbonylaminobutyric acid.

[0248] b: 4-(1-Pyrrolyl)-L-2-benzyloxycarbonylaminobutyramide

[0249] 1.2 g (4.0 mmol) of4-(1-pyrrolyl)-L-2-benzyloxycarbonylaminobutyric acid and 0.61 g (4.0mmol) of N-hydroxybenzotriazole ammonium salt, were dissolved togetherin 10 ml of DMF, admixed at 0° C. with 0.82 g (4.0 mmol) ofN,N′-dicyclohexylcarbodiimide and 0.68 ml (4.0 mmol) ofN-ethyldiisopropylamine, and the mixture was stirred at 0° C. for 30 minand at 20° C. for 3 h. The precipitated urea was filtered off withsuction and the filtrate was concentrated to dryness under reducedpressure. The crude product was purified by silica gel chromatography(CH₂Cl₂/CH₃OH/CH₃COOH:100/5/1). Yield: 0.89 g (74%).

[0250] c: 4-(1-Pyrrolyl)-L-2-aminobutyramide

[0251] Under inert gas, 0.80 g (2.65 mmol) of4-(1-pyrrolyl)-L-2-benzyloxycarbonylaminobutyramide, dissolved in 20 mlof methanol, was admixed with 80 mg of catalyst (10% Pd-C), and hydrogenwas then introduced until the Z protective group had been cleaved offcompletely. The catalyst was filtered off and the filtrate wasconcentrated, giving 0.4 g (90.5%) of4-(1-pyrrolyl)-L-2-aminobutyramide.

[0252] 2. Process Variant D)

Example 3

[0253]N-(1-carbamoyl-2-phenylsulfanylethyl)-2-pyridin-4-yl-1H-indole-5-carboxamide

[0254] 0.20 g (0.84 mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acidwas admixed with 0.21 g (1.07 mmol) of 2-amino-3-phenylsulfanylpropionicacid in 40 ml of DMF and, at 0° C., 0.66 g (1.27 mmol) ofbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate and0.37 ml (2.12 mmol) of N-ethyl-N,N-diisopropylamine were added, and thesolution was stirred at 20° C. for 2 h. The solution was concentratedunder reduced pressure and purified by medium pressure columnchromatography (CH₂Cl₂/CH₃OH:9:1). This gave 0.19 g (54%) ofN-(1-carbamoyl-2-phenylsulfanylethyl)-2-pyridin-4yl-1H-indole-5-carboxamide.

Example 9

[0255]3-Phenylaminoethyl-2-[(2-pyridin-4-yl-1H-indole-5-carbonyl)-amino]propionamide

[0256] a) L-2-Amino-3-phenylaminoethylpropionic acid

[0257] 54.8 g (0.209 mol) of triphenylphosphine were suspended in 600 mlof acetonitrile and, with exclusion of moisture, cooled to −35° C. to−45° C. At this temperature, 36.4 g (0.209 mol) of diethylazodicarboxylate were then added dropwise over a period of 50 min. Themixture was stirred at −35° C. for another 15 min. A solution of 50 g(0.209 mol) of N-benzyloxycarbonyl-L-serine in 500 ml of acetonitrilewas added dropwise to this mixture, the temperature being kept below−35° C. The mixture was then allowed to react at 5° C. for another 12 hand warmed to RT. The reaction solution was freed from solvent underreduced pressure and the crude product was purified by medium pressurechromatography over silica gel (DCM/AcCN:25/1). Removal of the solventgave 20.8 9. (yield 45%) of pure N-benzyloxycarbonyl-L-serine-β-lactone(see also Org. Synth. 1991 (70) 1ff.) in fine needles. Empirical formulaC₁₁H₁₁NO₄; M.W.=221.2; MS (M+H) 222.1.

[0258] Under a protective atmosphere of argon, 15.5 ml (63.51 mmol) ofN,O-bis(trimethylsilyl)acetamide were added to 7.3 ml (57.36 mmol) ofN-ethylaniline in 250 ml of acetonitrile, and the mixture was stirred at50° C. for 3 h. At 20° C., a solution of the above lactone (10.7 g,48.37 mmol) dissolved in 250 ml of acetonitrile was then added, and themixture was heated under reflux for 17 h. The solvent was removed andthe residue was then admixed with saturated sodium carbonate solution,the pH of the solution being kept below 9. The aqueous suspension waswashed with a little diethyl ether and then acidified to a pH of from 6to 7 using conc. hydrochloric acid, and adjusted to a pH of 5 usingNaHPO₄ buffer. The aqueous solution was then extracted repeatedly withethyl acetate. Evaporation of the solvents gave the desired product in ayield of 45% (7.4 g). Empirical formula C₁₉H₂₂N₂O₄; M.W.=342.4; MS (M+H)343.2.

[0259] At −10° C., 6.5 ml (89.1 mmol) of thionyl chloride were addeddropwise to 75 ml of methanol, and the mixture was stirred for 30 min.8.6 g (25.12 mmol) of L-2-aminoethyl-3-phenylaminopropionic acid,dissolved in 75 ml of methanol, were then added and the mixture wasstirred at −10° C. for 30 minutes and at room temperature for a further3 h. The solvents were evaporated and the residue was then taken up inethyl acetate and washed with sodium carbonate solution. Evaporation ofthe solvent and purification by flash chromatography (n-heptan/ethylacetate 7:3) gave 4.43 g (50% yield) of methylL-2-aminoethyl-3-phenylaminopropionic acid. Empirical formulaC₂₀H₂₄N₂O₄; M.W.=356.4; MS (M+H) 357.3.

[0260] To remove the protective group, 4.4 g (12.35 mmol) of theZ-protected derivative were dissolved in 500 ml of methanol, 100 mg ofcatalyst (10% Pd(OH)₂—C) were added under inert gas and hydrogen wasintroduced until the Z protective group had been cleaved off completely.The catalyst was filtered off and the filtrate was concentrated, giving2.8 g of L-2-aminoethyl-3-phenylaminopropionic acid (quantitative).

[0261] Empirical formula C₁₂H₁₈N₂O₂; M.W.=223.3; MS (M+H) 223.1.

[0262] Process Step b)

[0263] 0.63 g (2.64 mmol) of 2-pyridin-4-yl-1H-indole-5-carboxylic acid,prepared as in process variant B), was suspended in 150 ml of DMF andadmixed successively with 1.01 g (3.08 mmol) of TOTU and 0.63 ml (3.71mmol) of ethyldiisopropylamine. The mixture was stirred at RT for 20min, and 0.73 g (3.28 mmol) of methyl(S)-2-amino-3-phenylaminoethylpropionate, prepared according to a), wasadded to the resulting clear solution. The mixture was stirred underreduced pressure for 15 h and the methyl ester of the title compound wasthen isolated by flash chromatography over silica gel (DCM:MeOH=19:1).Yield: 0.44 g, empirical formula C₂₆H₂₆N₄O₃; M.W.=442.2; MS (M+H) 443.3.

[0264] 0.22 g (0.497 mmol) of the resulting methyl ester was dissolvedin 100 ml of methanol and cooled to 0° C., and 1.5 h of ammonia werethen introduced. The solution was allowed to stand at room temperatureovernight and the methanol was then evaporated. The crude product waspurified by flash chromatography over silica gel (DCM:MeOH=19:1). Yield:0.096 g (45.2%), empirical formula C₂₅H₂₅N₅O₂; M.W.=427.2; MS (M+H)428.3.

[0265] The compounds in Table 1 below were prepared analogously toProcesses A) to D). TABLE 1 Empirical MS Example Structure formula (M +H) Notes 1

M.W. = 473.58 C₃₁H₂₇N₃O₂ 474.2 pr.v.: A) pr.v.: C) 2

M.W. = 398.46 C₂₄H₂₂N₄O₂ 399.3 pr.v.: B) pr.v.: C) 3

M.W. = 416.50 C₂₃H₂₀N₄O₂S 417.1 pr.v.: A) pr.v.: D) 4

M.W. = 417.9 C₂₃H₁₉N₃O₃S 418.1 pr.v.: B) pr.v.: C) 5

M.W. = 431.51 C₂₄H₂₁N₃O₃S 432.1 pr.v.: B) pr.v.: C) 6

M.W. = 430.53 C₂₄H₂₂N₄O₂S 431.2 pr.v.: B) pr.v.: C) 7

M.W. = 516.47 C₂₃H₂₂N₄O₃. C₂HF₃O₂ 403.2 pr.v.: B) pr.v.: C) 8

M.W. = 475.50 C₂₄H₂₅N₅O₂. C₂H₄O₂ 416.5 pr.v.: B) pr.v.: C) 9

M.W. = 427.2; C₂₅H₂₅N₅O₂ 428.3

[0266] Pharmacological Examples IκB kinase ELISA:

[0267] The activity of the IκB kinase was determined using an ELISAcomprising a biotinilated substrate peptide containing the amino acidsequence in the protein IκB of serines 32 to 36 and a specific poly- ormonoclonal antibody (for example from New England Biolabs, Beverly,Mass., USA, cat.: 9240), which binds only to the phosphorylated form ofthe peptide IκB. This complex was immobilized on an antibody-bindingplate (coated with protein A) and detected using a conjugate of abiotin-binding protein and HRP (for example streptavidine HRP). Theactivity could be quantified using a standard curve with substratephosphopeptide.

[0268] Procedure:

[0269] To obtain the kinase complex, 10 ml of HeLa S3 cell extract S100were diluted with 40 ml 50 mM HEPES, pH 7.5, adjusted to 40% ammoniumsulfate and incubated on ice for 30 minutes. The precipitated pellet wasdissolved in 5 ml SEC buffer (50 mM HEPES, pH 7.5, 1 mM DTT, 0.5 mMEDTA, 10 mM 2-glycerophosphate), centrifuged at 20,000×g for 15 minutesand filtered through a 0.22 μm filter. The sample was applied to a 320ml Superose-6 FPLC column (Amersham Pharmacia Biotech AB, Uppsala,Sweden) which had been equilibrated with SEC buffer and was operated ata flow rate of 2 ml/min at 4° C. The fractions which corresponded to theelution time of the 670 kDa molecular weight standard were combined foractivation. Activation was achieved by a 45-minute-incubation with 100nM MEKK1Δ, 250 μM MgATP, 10 mM MgCl₂, 5 mM dithiothreitol (DTT), 10 mM2-glycerophosphate, 2.5 μM microcystin LR at 37° C. The activated enzymewas stored at −80° C.

[0270] The test substances, dissolved in DMSO (2 μl), were preincubatedat 25° C. with 43 μl of activated enzyme (diluted 1:25, in reactionbuffer 50 mM HEPES, pH 7.5, 10 mM MgCl₂, 5 mM DTT, 10 mMβ-glycerophosphate, 2.5 μM microcystin LR) for 30 minutes. 5 μl ofsubstrate peptide (biotin-(CH₂)C₆-DRHDSGLDSMKD-CONH₂(200 μM) were added,the mixture was incubated for one hour and the reaction was quenchedusing 150 μl of 50 mM HEPES, pH 7.5, 0.1% BSA, 50 mM EDTA, antibody[1:200]. 100 μl of the quenched reaction mixture or a standardphosphopeptide dilution series (biotin-(CH₂)₆-DRHDS[PO₃]GLDSMKD-CONH₂)were then transferred to a protein A plate (Pierce Chemical Co.,Rockford, Ill., USA) and incubated with shaking for 2 hours.

[0271] After 3 washing steps with PBS, 100 μl of 0.5 μg/ml ofstreptavidin HRP (horseradish peroxidase) (diluted in 50 mM HEPES/0.1%BSA) were added for 30 minutes. After 5 washing steps with PBS, 100 μlof TMB substrate (Kirkegaard & Perry Laboratories, Gaithersburg, Md.,USA) were added and the development of color was stopped by addition of100 μl of 0.18 M sulfuric acid. Absorption was measured at 450 nm. Thestandard curve was generated by linear regression according to a4-parameter dose-activity relation. Using this standard curve, theenzyme activity or their inhibition by test substances was quantified.

[0272] Method PKA, PKC, CK II

[0273] cAMP-dependent protein kinase (PKA), protein kinase C (PKC) andcasein kinase II (CK II) were determined using the corresponding testkits of Upstate Biotechnologie according to the instructions of themanufacturer at an ATP concentration of 50 μM. However, instead ofphosphocellulose filters, multi-screen plates (Millipore;Phosphocellulose MS-PH, cat. MAPHNOB10) with the correspondingaspiration system were used. The plates were then measured in a WallacMicroBeta scintillation counter. In each case, 100 μM of test substancewere used.

[0274] Each substance was tested in duplicate. The mean of the blank(without enzyme) was subtracted from the means (enzyme with and withoutsubstances), and the inhibition in % was calculated. IC₅₀ calculationswere carried out using the software package GraFit 3.0. The results areshown in Table 2 below. TABLE 2 Kinase inhibition at a substanceconcentration of 100 μM or IC₅₀ in μM Example IκB kinase PKA PKC CK IInumber IC₅₀ % inhibition % inhibition % inhibition 1 32 n.d. n.d. n.d. 20.61 24 15 35 3 0.55 35 39 37 4 0.50 42 33 47 5 1.8 55  8 27 6 4.9 60 5839 7 3.0 n.d. n.d. 18 9 1.0  0 23  0

1-8. (Canceled)
 9. A compound of the formula I

in any stereoisomeric form, or a physiologically acceptable saltthereof, where R¹, R² and R⁴ are, independently, hydrogen, halogen, oraryl; R⁵ is hydrogen; R³ is a radical of formula II

 in which D is —C(O)—; R⁷ is hydrogen; R⁸ is —(C₁-C₆)-alkyl, where alkylis straight-chain or branched and is unsubstituted or mono-, di- ortrisubstituted, independently of one another, by —N(R¹⁰)₂, where eachR¹⁰ is, independently, hydrogen, —(C₁-C₄)-alkyl, aryl, or a heterocyclehaving 5 to 12 ring members; and Z is —CONH₂ or —COO—R¹⁰ or a monocyclicor bicyclic 5-membered to 12-membered heterocyclic ring which is partlysaturated or completely saturated, wherein said heterocycle isunsubstituted or monosubstituted, disubstituted, trisubstituted ortetrasubstituted on carbon atoms by identical or different radicals fromthe group consisting of (C₁-C₈)-alkyl, phenyl-(C₁-C₄)-alkoxy, hydroxyl,oxo, halogen, nitro, amino or trifluoromethyl; R⁹ is, independently, anysubstituent identified above for R⁸; and R⁶ is a heterocycle having 5 to12 ring members, which is unsubstituted or substituted by —CN, —CF₃,halogen, —O—R¹⁰, —N(R¹⁰)₂, —NH—C(O)—R¹¹, —S(O)_(x)—R¹⁰, where x is theinteger zero, 1 or 2, —C(O)—R¹¹ or —(C₁-C₄)-alkyl-NH₂, and where R¹⁰ isas defined above and R¹¹ is —O—R¹⁰or —N(R¹⁰)₂.
 10. A compound as claimedin claim 9, wherein Z is pyrrole, furan, thiophene, imidazole, pyrazole,oxazole, isoxazole, thiazole, isothiazole, tetrazole,1,2,3,5-oxathiadiazole 2-oxide, triazolone, oxadiazolone, isoxazolone,oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-dione,5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, carboline or a benzo-fused or cyclopenta-,cyclohexa- or cyclohepta-fused derivative of any of the aboveheterocycles, which is unsubstituted or substituted by (C₁-C₄)-alkyl,methoxy, benzyloxy, hydroxyl, oxo, halogen, nitro, amino ortrifluoromethyl.
 11. A compound as claimed in claim 9, wherein Z isoxazole, isoxazole, 1,2,3,5-oxathiadiazole 2-oxide, oxadiazolone,isoxazolone, oxadiazolidinedione, 3-hydroxypyrrole-2,4-dione,5-oxo-1,2,4-thiadiazole or 1,3,4-oxadiazole, which is unsubstituted orsubstituted by (C₁-C₄)-alkyl, methoxy, benzyloxy, hydroxyl, oxo,halogen, nitro, amino or trifluoromethyl.
 12. A compound as claimed inclaim 9, wherein R⁸ is —CH₂—N(phenyl)₂.
 13. A compound as claimed inclaim 9, wherein R⁶ is pyrrole, furan, thiophene, imidazole, pyrazole,oxazole, isoxazole, thiazole, isothiazole, tetrazole,1,2,3,5-oxathiadiazole 2-oxide, triazolone, oxadiazolone, isoxazolone,oxadiazolidinedione, triazole, 3-hydroxypyrrole-2,4-dione,5-oxo-1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, carboline or a benzo-fused or cyclopenta-,cyclohexa- or cyclohepta-fused derivative of any of the aboveheterocycles, which is unsubstituted or substituted by —N(R¹⁰⁾ ₂,wherein R¹⁰ is —(C₁-C₄)-alkyl.
 14. A compound as claimed in claim 9,wherein R⁶ is unsubstituted or substituted pyrrole, pyrazole, pyridine,pyrazine or pyrimidine.
 15. A compound as claimed in claim 9, whereinR¹, R² and R⁴ are hydrogen.
 16. A method for the treatment of a disorderin the course of which an increased activity of NFKB is involved, whichcomprises administering to a host in need of the treatment an effectiveamount of a compound as claimed in claim 9, wherein the disorder isjoint inflammation.
 17. A method as claimed in claim 16, wherein thejoint inflammation is arthritis, rheumatoid arthritis or other arthriticcondition.
 18. A method as claimed in claim 17, wherein the otherarthritic condition is rheumatoid spondylitis, gouty arthritis,traumatic arthritis, rubella arthritis, psoriatic arthritis, orosteoarthritis.
 19. A method for the treatment of a disorder in thecourse of which an increased activity of NFKB is involved, whichcomprises administering to a host in need of the treatment an effectiveamount of a compound as claimed in claim 9, wherein the disorder isacute synovitis, tuberculosis, atherosclerosis, muscle degeneration,cachexia, Reiter's syndrome, endotoxaemia, sepsis, septic shock,endotoxic shock, gram negative sepsis, gout, or toxic shock syndrome.20. A method for the treatment of a disorder in the course of which anincreased activity of NFKB is involved, which comprises administering toa host in need of the treatment an effective amount of a compound asclaimed in claim 9, wherein the disorder is chronic pulmonaryinflammatory disease.
 21. A method as claimed in claim 20, wherein thechronic pulmonary inflammatory disease is asthma or adult respiratorydistress syndrome.
 22. A method for the treatment of a disorder in thecourse of which an increased activity of NFKB is involved, whichcomprises administering to a host in need of the treatment an effectiveamount of a compound as claimed in claim 9, wherein the disorder issilicosis, pulmonary sarcoidosis, bone resorption disease, reperfusioninjury, graft versus host reaction, allograft rejection or leprosy. 23.A method for the treatment of a disorder in the course of which anincreased activity of NFKB is involved, which comprises administering toa host in need of the treatment an effective amount of a compound asclaimed in claim 9, wherein the disorder is a viral infection.
 24. Amethod as claimed in claim 23, wherein the viral infection is HIV,cytomegalovirus, influenza, adenovirus, or a Herpes virus.
 25. A methodfor the treatment of a disorder in the course of which an increasedactivity of NFKB is involved, which comprises administering to a host inneed of the treatment an effective amount of a compound as claimed inclaim 9, wherein the disorder is a parasitic infection.
 26. A method asclaimed in claim 25, wherein the parasitic infection is malaria.
 27. Amethod as claimed in claim 26, wherein the malaria is cerebral malaria.28. A method for the treatment of a disorder in the course of which anincreased activity of NFKB is involved, which comprises administering toa host in need of the treatment an effective amount of a compound asclaimed in claim 9, wherein the disorder is a yeast or fungal infection.29. A method as claimed in claim 28, wherein the infection is fungalmeningitis.
 30. A method for the treatment of a disorder in the courseof which an increased activity of NFKB is involved, which comprisesadministering to a host in need of the treatment an effective amount ofa compound as claimed in claim 9, wherein the disorder is fever ormyalgia due to infection.
 31. A method for the treatment of a disorderin the course of which an increased activity of NFKB is involved, whichcomprises administering to a host in need of the treatment an effectiveamount of a compound as claimed in claim 9, wherein the disorder isacquired immune deficiency syndrome (AIDS) or AIDS related complex. 32.A method for the treatment of a disorder in the course of which anincreased activity of NFKB is involved, which comprises administering toa host in need of the treatment an effective amount of a compound asclaimed in claim 9, wherein the disorder is keloid or scar tissueformation.
 33. A method for the treatment of a disorder in the course ofwhich an increased activity of NFKB is involved, which comprisesadministering to a host in need of the treatment an effective amount ofa compound as claimed in claim 9, wherein the disorder is pyresis ordiabetes.
 34. A method for the treatment of a disorder in the course ofwhich an increased activity of NFKB is involved, which comprisesadministering to a host in need of the treatment an effective amount ofa compound as claimed in claim 9, wherein the disorder is inflammatorybowel disease.
 35. A method as claimed in claim 34, wherein theinflammatory bowel disease is Crohn's disease or ulcerative colitis. 36.A method for the treatment of a disorder in the course of which anincreased activity of NFKB is involved, which comprises administering toa host in need of the treatment an effective amount of a compound asclaimed in claim 9, wherein the disorder is multiple sclerosis or headtrauma.
 37. A method for the treatment of a disorder in the course ofwhich an increased activity of NFKB is involved, which comprisesadministering to a host in need of the treatment an effective amount ofa compound as claimed in claim 9, wherein the disorder is psoriasis,Alzheimer's disease, a carcinomatous disorder, cardiac infarct, chronicobstructive pulmonary disease or acute respiratory distress syndrome.